This invention is generally in the area of drug delivery systems and is particularly related to reversible microencapsulation of drugs by certain 2,5-diketo-derivatives of piperazine.
Delivery of drugs has been a major problem for many years. It is particularly a problem when the compound to be delivered is unstable under the conditions encountered when administered to the patient, prior to reaching its targeted location. For example, it is preferable in many cases to administer drugs orally, especially in terms of ease of administration, patient compliance, and decreased cost. However, many compounds are ineffective or exhibit low or variable potency when administered orally. Presumably this is because the drugs are unstable to conditions in the digestive tract or because they are inefficiently absorbed.
The field of oral drug delivery covers a broad range of delivery systems ranging from simple mechanical carriers such as pressed tablets which transport compounds that can be safely and efficiently delivered through the stomach, to enteric coatings which delay the release of the encapsulated compound to later in the digestive process and lower in the gastrointestinal tract. A variety of enteric coatings have been used to encapsulate and protect the drug prior to reaching the small intestine. In some cases these are effective. However, there are drugs that are also unstable to the conditions present in the small intestine and therefore must be administered in much higher dosages if the drug is to be released in the small intestine for an effective amount to penetrate to the bloodstream. In these cases, it is necessary to have a mechanism whereby the coating is not only stable to the conditions present in the digestive tract, as well as to the conditions under which it is stored prior to administration to the patient, but which allows the encapsulated drug to pass into the bloodstream.
Other factors in drug delivery system design include the requirements that the system must be non-toxic, non-reactive with the drug to be delivered, not too expensive or difficult to manufacture, formed of readily available components, and consistent with respect to final composition and physical characteristics, including stability and release rate. The system must also be formed of materials that are easily removed by normal metabolic processes.
A number of different systems have been proposed, most based on peptides or biodegradable natural or synthetic polymers, such as the natural polysaccharides or polylactic acid, polyglycolic acid, polyorthoesters, or polyanhydrides, alone or within an appropriate enteric coating, for example, as described by EPA 0 333 523 by The UAB Research Foundation and Southern Research Institute. With the exception of this synthetic polymeric system and two protein-based systems, the proteinoid microspheres described in Steiner and Rosen U.S. Pat. Nos. 4,925,673, 4,983,402, and 4,976,968 and the zein microspheres described in PCT application WO 91/06287 by Enzytech, none of these systems is stable to conditions in the stomach. Only the proteinoid system is designed particularly to be stable to the lower pH of the stomach and unstable to the higher pH of the blood.
The most desirable delivery system from a manufacturing standpoint is one that is self assembling from simple, chemically defined precursors, which are stable over the pH, temperature and solvent range of interest, yet resistant to rapid protease attack. Ideally, these precursors are economical and available, using available technology, in production volume.
One of the best known self-assembling encapsulation systems is the amino acid polymer self-assembling microcapsules first pioneered by Dr. Sidney Fox (Molecular Evolution and the Origin of Life). The initial experiments were with "proteinoids", a "linear thermal condensation polymer of a mixture of naturally occurring amino acids", the same system subsequently patented by Steiner and Rosen for drug delivery. While this did in fact demonstrate a capacity for self-organization under conditions plausible for early evolution, the behavior of the system is undesirable as an encapsulation technology. The stochastic nature of the precursors and the further stochastic nature of self assembly of linear polymers are inappropriate for a controllable process.
Accordingly, there remains a significant economic and medical need for an effective method for the oral delivery and release of therapeutic agents which are poorly absorbed by or unstable in the gastrointestinal tract.
It is therefore an object of the present invention to provide a system for drug delivery.
It is a further object of the present invention to provide a system which, by intentional modifications to its structure, can be made to be stable or unstable in a variety of physiological conditions.
It is another object of the present invention to provide a system which is self-assembling and can be manufactured economically from currently available reagents.